Fibroblast growth factor-2–mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma

Abstract

In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchymal-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.

Prognostic importance of FGF2 and FGFR1 expression for patients affected by ameloblastoma

“…Although FGF interacts with many cellular components, the activation of the MAPK and the activation of the PI3K/AKT pathways are two of the most important roles played by these proteins. Moreover, FGF‐FGFR also stimulates the activation of Src kinase, STATs, Crk, and ribosomal S6 protein kinase (RSK), among others …”

“…The expression of FGF‐FGFR has been shown to be altered in a diverse number of human neoplasms; in many cases, these changes represent important prognostic factors . For odontogenic tumors, few studies attempted to investigate the distribution and importance of these molecules.…”

Astragaloside IV attenuates inflammatory injury and promotes odontoblastic differentiation in lipopolysaccharide‐stimulated MDPC‐23 cells and rat pulpitis

“…FGF2/ERK signaling has been reportedly participates in cell proliferation, differentiation, and inflammation in various pathophysiological processes . AS‐IV administration significantly decreased FGF2 and p‐ERK levels in LPS‐stimulated MDPC‐23 cells (Figure A).…”

Lapachol is a novel ribosomal protein S6 kinase 2 inhibitor that suppresses growth and induces intrinsic apoptosis in esophageal squamous cell carcinoma cells

“…Recently, FGF‐mediated MAPK signaling activation was shown to promote tumor growth in ESCC (Chen et al, ; Maehara et al, ), and EGFR inhibitors have been used for ESCC chemotherapeutics (Hu et al, ; Lee et al, ). Therefore, the FGF or EGF signaling pathway is important for ESCC therapy.…”